Orthogonally Protected Diaminocyclopentenones as Synthons: Total Synthesis of (±)-Agelastatin A

Natural products containing aminocyclopentanes are common secondary metabolites, often biologically active. This work aims at the preparation of a useful synthon for total synthesis containing orthogonally protected amines. To this end, furfural and two amines were employed to form mixed trans-4,5-diaminocyclopentenones promoted by Cu(OTf)2. The selected amines can be orthogonally deprotected, allowing selective modification of the amines on the cyclopentane core. Their utility was showcased for the total synthesis of highly complex (±)-Agelastatin A.


General information S2
General procedure for the reaction optimization S2 General procedure for the preparation of mixed trans-4,5diamino-cyclopent-2-enones S2 General Procedure for the Preparation of 2-amino-4-thio cyclopentenones S10 Attempts at protecting the enone 1c towards the total synthesis of Agelastatin A S15 Total Synthesis of (±)-Agelastatin A S17 Enantioselective attempts S24 NMR Characterization S31 S2

General information:
All solvents were distilled prior to use. All reagents were used as received from commercial suppliers, unless otherwise stated. 1 H and 13 C NMR spectra were acquired on Bruker MX300 spectrometer. HPLC analysis was performed on a Thermo Scientific Dionex Ultimate 3000 apparatus with a LPG-3400SD Pump, a UV MWD-3000(RS) detector and an autosampler ACC-3000, equipped with a 20 μL loop, using a reversed-phase EC 250/4 Nucleodur 100-5 C18ec column (250×4 mm, 5 μm) Thermo ScientificTM DionexTM. Shimadzu LC-20AT prominence liquid chromatograph with SPD-M20A diode-array detector was used alongside HPLC CHIRALPAK® IC 5 μm 4.6 mm x 250 mm chiral HPLC column for chiral analysis. Chromatograms were processed with Shimadzu LC solution software. Structural assignments were made with additional information from gCOSY, gHSQC, and gHMBC experiments

General procedure for the reaction optimization
To a solution of Cu(OTf)2 (7.5 mg, 10 mol%) in water (0.2 mL) was added dibenzylamine (41 mg, 0.20 mmol, 1 equiv.), morpholine (1 or 2 equiv.), and furfural (20 mg, 0.2 mmol). The reaction was allowed to stir vigorously at room temperature for 5 minutes. Then the reaction mixture was diluted with water (2 mL) and extracted with MTBE (3 × 2 mL). The combined organic phases were dried with MgSO4, the solvent was evaporated under reduced pressure and the crude mixture was purified by column chromatography to quantify the product yield. Table S1. Reaction optimization towards mixed diaminocyclopentenones. [a] Entry Time (min) Solvent Morpholine (equiv.) 1a (%)

General procedure for the preparation of mixed trans-4,5-diamino-cyclopent-2-enones
To a solution of Cu(OTf)2 (80 mg, 10 mol%) in water (2 mL) was added amine A (1.04 mmol, 1 equiv.), amine B (2.08 mmol, 2 equiv.), and furfural (200 mg, 2.08 mmol). The reaction was allowed to stir vigorously at room temperature for 5 minutes. Then the reaction mixture was diluted with water (18 mL) and extracted with MTBE (3 × 20 mL). The combined organic phases were dried with MgSO 4 , the solvent was evaporated under reduced pressure and the crude mixture was purified by column chromatography.

General Procedure for the Preparation of 2-amino-4-thio cyclopentenones
The mixed CP (0.2 mmol, 1 equiv) was dissolved in MeOH (2 mL) Then, was added 2 equivalents of the corresponding substituted thiol (0.4 mmol) and KO t Bu (5.6 mg, 0.25 equiv, 0.05 mmol). The mixture was stirred at room temperature under nitrogen atmosphere for 2h. Afterwards, the crude was filtered through a short plug of celite and the filter cake was washed with DCM (6 mL). To the filtrate was added AcOH/NaOAc buffer solution at pH 5 (2 mL) and brine (4 mL). The organic layer was separated, and the aqueous layer was further extracted with DCM (2×6 mL), and the combined organic layers were dried with anhydrous MgSO 4 , filtered and concentrated under reduced pressure. The crude mixture was further purified by column chromatography.

2-(dibenzylamino)-4-methoxycyclopent-2-en-1-one (S1)
The titled compound was prepared according to general procedure without the use of any thiol and using 1 equiv of NaOMe as base. The crude mixture was purified by flash chromatography using hexane:ethyl acetate (9.5:0.5 to 8:2) affording 33 mg (54%) of pure product as a brown oil.
Attempts at protecting the enone 1c towards the total synthesis of Agelastatin A

Preparation of N-5-(dibenzylamino)-4-oxocyclopent-2-en-1-yl)-1H-pyrrole-2-carboxamide (9)
To a solution of 3 (20 mg, 0.51 mmol) in THF (0.5 mL) was added Cs2CO3 (17 mg, 0.51 mmol, 1 equiv) and the reaction was allowed to stir at room temperature under inert atmosphere. The reaction was monitored by TLC until full consumption of starting material. The reaction was diluted with AcOEt (3 mL) and washed with brine (4 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude mixture was re-dissolved in THF (1 mL) and added to a reactor containing Pd/C (2 mg). N-methyl-1H-imidazole-1-carboxamide (13 mg, 1 mmol, 2 equiv) was added to the reaction mixture. The reactor was purged with nitrogen and filled with H2 (8 bar). After 12h the reaction mixture was filtered through Celite and concentrated under reduced pressure. The crude was further purified by flash chromatography using CH2Cl2:MeOH (9:1) affording 8 mg (58 %) of pure product as a white solid.

Enantioselective attempts:
Firstly enantiomeric attempts at obtaining the desired trans-4,5-diamino-cyclopent-2-enones focused on the use of chiral ligands as depicted in Table S5. Unfortunately no ee was observed using a variety of pybox and box ligands in different solvents. Additionally, the reactions were often incomplete. Also, due to the reversible nature of the CP systems, in several cases the chromatogram exhibits a furfural peak, despite being pure by 1 H-NMR.  [a] furfural (20 mg, 0.2 mmol), amine (2 equiv.), Ligand (x equiv), anhydrous solvent (0.2 mL) The ligand was stirred with the metal for 18h prior to the reaction. [b] No product was observed.

S29
Selected HPLC-DAD analysis of crude mixture from attempts at enantioselective reaction towards DCP 2 (Entry 13,